Complete Meals & GI (Non-)Sense, Glutamine & GLP-1, Low Thyroid & High Trigs, N-3 vs. N-6 Interactions, Optimal DHA Dosage in Kids W/ NAFLD, Selenium vs. Aluminum Toxicity

While this is not the exact combination of chicken breast, mashed potatoes and salad in the first one of today's news items, it's more than likely that the predicted GI (and thus probably what you would find if you looked it up in a table) overestimates the postprandial glucose response to this meal by ~50% and says absolutely nothing about the insulin response. It looks like complex meals and over-simplified theories, don't mix well, at all ;-)

78% that's the SuppVersity Figure of the Week and actually part of the additional information I provided on one of today's On Short Notice items. It's the increase in coronary heart disease risk women with subclinical hypothyroidism have compared to their peers with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2013). In conjunction with other more or less recent studies, such as Mitchel's, Hsu's and Sahai's paper confirming the previously often talked about but not well-established 2-fold increase in congenital hypothyroidism from the early 1990s to the first years of the new millennium (Mitchel 2011), the predictive value of high TSH levels in the first trimester (early pregnancy hypothyroidism) for adverse pregnancy outcomes (Schneuer. 2013), the 30% risk increase in all-cause mortality in both women and men with subclinical hypothyroidism Tseng et al. reported in their paper earlier this year or the impairment of spatial working memory (Yin. 2013), Asvold's results only add to the evidence that the potential pitfalls of an increasingly prevalent metabolic dysfunction may have been ignored way too long.

• More GI lovin' - On the menu today: Mashed potaoes with chicken, rapeseed oil or both (Hätönen. 2011) - I thought a mini-follow-up on Friday's post on the GI would be nice, 'cause some of you have not without reason been complaining that not everyone would eat pure white bread, like my students do.
  
  

  

  Figure 1: The real (=measured) GI of a meal does differ significantly from the theoretical prediction. So, even if the concept was worth bothering, the GIs of complete meals simply wrong, if they are not measured (Hötönen. 2011).

  Moreover, the mere fact that the scientists from the Department of Lifestyles and Participation at the National Institute for Health and Welfare in Helsinki, Finland, found that the addition of chicken breast, rapeseed oil and a salad, individually and in combination, had the GI of a meal containing six mashed potatoes (this was the parameter that was held constant) induced more than twofold changes in GI, with the addition of chicken breast having the greatest deviation from the predicted value in this group of 11 (initially 12) healthy subjects, three men and nine women, aged 36.2 (SD 14.1) years with a BMI of 21.3 (SD 1.7) kg/m² and normal glucose tolerance (see figure 1).
  
  Now given the fact that most data on the GI of complete meals has never been measured, but is actually based on the same predictions the scientists used, it stands to reason that...
  

  [...] this highlights the problems encountered when predicting the GI values of mixed meals. The protein com-ponent of the mixed meal evoked the largest insulinaemic responses and markedly increased the II of the mixed meal containing protein. However, introducing fat into the meal decreased the effect of protein on the insulinaemic responses (Hätönen. 2011)

  So, this does not simply bust the idea that you could calculate the GI, it does likewise show you that people who are still overtly scared of insulin (which is hillarious as long as you are insulin sensitive) are doing he exact wrong thing, when they make food-choices based on GI: Whey protein would in that case be in as much a no-go as simply eating a chicken breast with your mashed potatoes would be, because other than what most people believe, it does increase the insulin spike and thus reduce the glycemic index by allowing your body to clear the glucose more efficiently from the circulation.
  
  Suggested reads: The red box in the "Whey is More Insulinogenic than White Bread" post on the partitioning effects of BCAAs and yesterday's Facebook post on the anti-Alzheimer's effects of insulin.

• 

  Suggested read: Amino Acids for Super Humans the purported ergogenic effects of l-glutamine

  30g of oral glutamine have similar effects on GLP-1 as 75g of glucose (Greenfield. 2008) - Still a follow up on the GI discussion, I think you may be interested in. If you are someone who follows the questionable practice of ingesting large boluses of glutamine in the futile believe that this would increase your gains or speed up recovery, you may be pleased to hear that only 30g of oral l-glutamine produced an increase in the "Fat Burning Satiety Hormone GLP-1" (read more on GLP-1) that's on a gram to gram basis more pronounced than in response to insulin (0.41pmol/L per gram glucose vs. 0.75pmol/L per gram of glutamine; in 8 healthy subjects).
  
  Before you go and buy tons of glutamine, you should however consider that GIP, the pro-insulinogenic peptide and glucagon (ramps up gluconeogenesis in the liver) were likewise increased by the ingestion of this bolus of glutamine. It is therefore no wonder that glutamine has never been shown to be a "fat burner". Nonetheless, a 1999 study by Bowtell et al. would suggest that it may come handy to replenish liver and muscle glycogen after a workout (8g alone did increase glucose storage after a workout to a similar degree as a 18.5% glucose polymer solution and additional 25% glucose storage mostly in the liver, when both were coingested; cf. Bowtell. 1999). And if you don't care about that - your gut integrity could also be a reason to consider supplementation in the vicinity of particular strenuous or length workouts (see "Shedding Some Light on the Leaky Gut <> Exercise Connection") 

• Practical relevance? Based on data from a 12-year longitudinal study, even women with subclinical hypothyroidism have 76% risk for coronary heart disease (p = 0.005), than women with spot on TSH levels of 0.5-1.5mU/L (Asvold. 2013). And even women well within in the "normal range" (TSH of 1.5-2.4mU/l) have a 41% higher risk of heart disease, although this is only borderline significant (p = 0.08). For men the TSH level alone had not predictive value. Spec. w/ regards to T3, there are also reports of increased incidence of ventricular disfuntion (Cassetti. 2009), increased cardiac death in CVD patients (Iervasi. 2003) and impaired recovery after a stroke (Alevizaki. 2007). We do yet have to be cautious, here as "low T3" syndrome could as well be the consequence of overall inflammation and the association does not tell us anything about what's the chicken and the egg.
  Low thyroid, high triglyceride (Hashimoto. 2013) -- If you are wondering why on earth your trigs won't come down, it may well be that it's the absence of sufficient amounts of thyroid hormone. I a soon-to-be-published paper in Endocrinology scientists from the Gunma University in Maebashi, Gunma, Japan, report that thyroid hormone regulates the expression of a Stearoyl-CoA desaturase-1 (SCD-1) which controls the production of trigs from carbohydrates.
  
  Surprisingly the 75% increase due to hypothyroidism and the 75% decrease in SCD-1 mRNA expression (both compared to a euthyroid state) the scientists observed in rodents in response to the administration of T3 were not mediated by receptor binding, but simply as a down-stream effect of direct modifications of the SCD-1 gene promoter between -124 and -92 bp by T3.
  
  On a related side note: It is actually the last mentioned mechanism which is the major new finding in the study at hand and not the fact that T3 can reduce the conversion of carbohydrates to triglicerides that is the actual news here. After all, the latter is something scientist should know, but obviously like to forget about ever since the late 1999s (Waters. 1997)

• Omega-6 intake and not low omega-3 intake is the problem (Liou. 2007) -- Another older study, but one I am posting in response to a discussion some of you are having about omega-3 (ALA) intake in the post about safflower oil and DHT, because I simply feel that it's necessary to shed some light  on the erroneous assumption that by simply upping your intake of omega-3s or fish oil intake you could get away without decreasing your omega-6 intake, which in and out of itself will already increase the amount of anti-inflammatory omega-3 fatty acids (supplementation of DHA can still be advisable, specifically if you are a vegetarian).
  
  

  

  Figure 2: Effect of 4 weeks of high (red) vs. 4 weeks of low (green) linoleic acid (n-6) intake on short and long-chain omega-3 plasma phospholipid content in healthy men (Liou. 2007)

  In 2007, already Liu et al. conducted a very interesting experiment in the course of which they fed healthy men diets with identical amounts of omega-3 fatty acids (1% of the total energy intake), but two different amounts of linoleic acid (omega-6) and found that the high omega-6 intake (10.1% vs. 3.8% of the total energy intake) alone decreased the total amount of EPA among the plasma phospholipids (the major long-chain omega-3 fatty acid in fish oil), not just the ratio of omega-3 to omega-6, in the blood of their 29-45 year-old subjects by more than 25% (see figure 2). The paradoxical effect on DHA, on the other hand, would warrant further investigation, and underlines how reliant we are - if anything on the intake of pure DHA, which dropped in consequence to the test diet, which was devoid of fatty fish, while the original diet of the non-vegetarian subjects had fish in it.
  
  In this context, I would also like to point out that DHA is exactly where real fish is far superior to fish oil caps, because it has a way more favorable EPA:DHA ratio than fish oil caps. Salmon fillets for example have - depending on the fatty acid source in the diet 8.5g : 13.8g, 4.4g : 7.8g and 1.5g : 2.9g (all values per 100g) when the feed contains fish oil, fish and rapeseed and fish + rapeseed and rapeseed, only.
  
  And while the ratios are similar regardless of the chow, the data from the Seierstad et al. clearly shows that the fatty acid content of the diets can induce almost 5-fold differences in terms of the total DHA content and the omega-3 to omega 6 ratio (fish oil diet: 6.5, fish oil + rapeseed: 1.7, rapeseed: 0.6) of salmon fillets (Seierstad. 2003). 

• It does not take much: 500mg DHA not more effective than 250mg  (Nobili. 2013) -- At least if it comes to its beneficial effects against liver steatosis in children  (mean age 11 years; BMI 26.6kg/m² and 24.4kg/m², in the low and high dose groups respectively with with NAFLD, the amount of DHA does not appear to be so important. According to the results of their 2-year registered controlled trial, both 250mg and 500mg of Docosahexaenoic acid lead to identical and profound reductions in the odds ratio of developing more severe steatosis during the study period.
  
  

  

  Figure 3: Odds ratio (comparing DHA supplement vs. placebo) of more severe vs. less severe liver steatosis determined every 6 months during the 24-month study period (Nobili. 2013)

  If you take a closer look at the data in figure 3, you will even have to concede that the lower dosage did a better job - while the mean odds ratios were only marginally lower in the 250mg DHA group, the extremely high standard deviations in the 500mg DHA would suggest that the 250mg dose appears to be more reliable. In this regard it may be interesting that the increase in serum DHA did mirror the dosages. With a 0.65% and 1.15% increase in DHA those were about 2x higher in the 20 boys and girls in the high dose group compared to the 20 kids in the control group who received a 290 mg linoleic acid germ oil supplement "placebo" (by the way, a monosaturated fatty acid placebo would have been more of a placebo than 290mg of omega-6)
  
  In view of the fact that the changes in triglycerides, ALT, HOMA-IR and BMI (which was not even different from the placebo group) were likewise identical, it does not appear as if anything that goes beyond the amount you will find in 2x cheap fish oil caps, or 10g even of the cheapest salmon fillet (see last paragraph of previous item) would be necessary to ellicit the anti-steatosis effect of fish oil - since those kids weight on average 55kg, an adult may want to add in another fish oil cap to get up to 360mg DHA per day or simply eat his fatty fish once or twice a week.

• Selenium ameliorates aluminum toxicity (Viezeliene. 2013) -- With the whole upheaval about the potential negative side effects of the aluminum in vaccines, the formerly overlooked yet well-known neurotoxic (Exley. 1992; Gupta. 2005), hepatotoxic (Abubakar. 2003; Perez. 2005) and nephrotoxic metal (Geyikoglu. 2013) has all of a sudden returned to the center of public interest.
  
  Therefore I thought that you will be interested in the results of a study that's going to be published in the next issue of the Journal of Trace Elements in Medicine and Biology - irrespective of whether you believe, like Tomljenovic and Shaw that
  

  "the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community"(Tomljenovic. 2011)

  After all, vaccines are not the only potential source of aluminum in our environment, so that the ameliorative effects (all values remained normal in the aluminum exposed group, while there were 30%, 55% and 42% increases in GSH in the animals who received only the selenium injection) the co-administration of supplemental selenium had on the GSH reductions in liver, kidney and brain of Balb/c mice weighing 20–25g who were exposed (by i.p. injection)to AlCl3 (25 mg Al(3+)/kg body mass) for 16h could be important, regardless of whether you do or don't intend to get vaccinated.
  
  

  

  There is more about selenium at the SuppVersity, for example on its pro-fertility effects, and its anti-corrosive effects in the brain.

  That said, the dosage requirements necessary to maintain healthy GSH levels are probably much lower than the hillarious (for a healthy individual) in the study at hand 1,250µg/kg body weight of sodium selenite (Na2SeO3). Considering the elemental selenium content in Na2SeO3, the latter would equal to ~3,650µg - unquestionably WAY too much (remember this was a one-time dosage that was specifically co-administered w/ the aluminum). Even the 'no observed adverse effect' level for a 70kg man of intake which is ~1000µg/d (Whanger. 1999) appears unnecessarily high, so that the consumption of a handful of brazil nuts once or twice a week and/or other high selenium foods such as tuna, cod, oysters, shrimp, but also eggs, meats, poultry, mushroom and onions on a regular should suffice to get what you need, to fortify yourself against the constant assault of heavy metals.
  
  What would be interesting, though, is a study into the effects of adding selenium to the "safe" aluminum in vaccines. I mean, you cannot seriously tell me that we could not afford doing that and if it reduced any toxicity issues, why not?

That's about it for today, I did not post all too many new facebook news as of yet (I mean, come on, it's Saturday ;-), but if you are into medicinal horror-stories, you will certainly like the story about the flesh eating killer fungus. If you prefer microbes over fungi, you are probably better off with the latest insights into the associations of certain gutbacteria with the incidence of stroke. And if you are more into other aspects of the digestive tract you may be interested in the effects of gastric emptying time on postprandial gylcemia and insulin release.

If none of those news is to your liking, I suggest you either wait for me to post something else (could be happening within the next hours at www.facebook.com/SuppVersity), or simply enjoy the weekend and come back tomorrow when you are rested for another (hopefully) enlightening SuppVersity post.

References:

• Abubakar  MG,  Taylor  A,  Ferns  GA.  Aluminium  administration  is  associated  with enhanced  hepatic  oxidant  stress  that  may  be  offset  by  dietary  vitamin  E  in  the rat. Int J Exp Pathol 2003;84:49–54.
• Asvold BO, Bjøro T, Platou C, Vatten LJ. Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT Study in Norway. Clin Endocrinol (Oxf). 2013 Dec;77(6):911-7.
• Bowtell JL, Gelly K, Jackman ML, Patel A, Simeoni M, Rennie MJ. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. J Appl Physiol. 1999 Jun;86(6):1770-7.
• Cassetti G, Pinelli M, Bindi M, Bianchi M, Castiglioni M. [Low T3 syndrome and left ventricular diastolic function]. G Ital Cardiol (Rome). 2009 Aug;10(8):553-7. 
• Exley  C,  Birchall  JD.  The  cellular  toxicity  of  aluminium.  J  Theor  Biol 1992;159:83–98.
• Geyikoglu  F,  Turkez  H,  Ozhan  Bakir  T,  Cicek  M.  The  genotoxic,  hepa- totoxic,  nephrotoxic,  haematotoxic  and  histopathological  effects  in  rats after aluminium chronic intoxication. Toxicol Ind Health 2013;15.
• Greenfield JR, Farooqi IS, Keogh JM, Henning E, Habib AM, Blackwood A, Reimann F, Holst JJ, Gribble FM. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2009 Jan;89(1):106-13.
• Gupta  VB,  Anitha  S,  Hegde  ML,  Zecca  L,  Garruto  RM,  Ravid  R,  et  al.  Alu- minium  in  Alzheimer’s  disease:  are  we  still  at  a  crossroad?  Cell  Mol  Life  Sci 2005;62:143–58.
• Hashimoto K, Ishida E, Miura A, Ozawa A, Shibusawa N, Satoh T, Okada S, Yamada M, Mori M. Human Stearoyl-CoA Desaturase 1 (SCD-1) Gene Expression Is Negatively Regulated by Thyroid Hormone without Direct Binding of Thyroid Hormone Receptor to the Gene Promoter. Endocrinology. 2013 Dec 7.
• Hätönen KA, Virtamo J, Eriksson JG, Sinkko HK, Sundvall JE, Valsta LM. Protein and fat modify the glycaemic and insulinaemic responses to a mashed potato-based meal. Br J Nutr. 2011 Jul;106(2):248-53. 
• Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate A, Donato L. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation. 2003 Feb 11;107(5):708-13.
• Liou YA, King DJ, Zibrik D, Innis SM. Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men. J Nutr. 2007 Apr;137(4):945-52. 
• Mitchell ML, Hsu HW, Sahai I; Massachusetts Pediatric Endocrine Work Group. The increased incidence of congenital hypothyroidism: fact or fancy? Clin Endocrinol (Oxf). 2011 Dec;75(6):806-10.
• Perez  G,  Pregi  N,  Vittori  D,  Di  Risio  C,  Garbossa  G,  Nesse  A.  Aluminium  expo- sure  affects  transferrin-dependent  and  -independent  iron  uptake  by  K562  cells. Biochim  Biophys  Acta  2005;1745:124–30. 
• Schneuer FJ, Nassar N, Tasevski V, Morris JM, Roberts CL. Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes. J Clin Endocrinol Metab. 2013 Sep;97(9):3115-22.
• Seierstad SL, Seljeflot I, Johansen O, Hansen R, Haugen M, Rosenlund G, Frøyland L, Arnesen H. Dietary intake of differently fed salmon; the influence on markers of human atherosclerosis. Eur J Clin Invest. 2005 Jan;35(1):52-9.
• Waters KM, Miller CW, Ntambi JM. Localization of a negative thyroid hormone-response region in hepatic stearoyl-CoA desaturase gene 1. Biochem Biophys Res Commun. 1997 Apr 28;233(3):838-43. 
• Whanger P, Vendeland S, Park Y-C & Xia Y. Metabolism of sub-toxic levels of selenium in animals and humans. Annals of Clinical Laboratory Science. 1996;26, 99-113.

SuppVersity Science Round-Up Seconds: Supplement-Drug Interactions, Exercise and Psychology, Running vs. O-Lifting & Right Ventricular Hypertrophy, News on the N3-to-N6 Ratio, the CYP Enzymes, Endocannabinoids & Telomeres

The SuppVersity Science Round-Up every Thursday live on Carl Lanore's Super Human Radio -- tune in live at 1PM (EST=  6PM GMT)!

I hope that most of you have already had a chance to listen to yesterday's installment of the SuppVersity Science Round Up on Super Human Radio. In case you didn't, or have been waiting for me to post the link to the podcast (just a reminder: you can always download the latest show, from the navigation bar on the right, where it says: "Physical Culture for your Ears"), I'd suggest you go and download the podcast either now, or after going through today's SuppVersity Science Round Up Seconds.

The "Seconds" are as the name implies no "leftovers", but actually yet another selection from the selection of god knows how many interesting newsbits I usually pile up for the short 1h show, Carl and I are doing every Thursday. I would therefore encourage everyone to do both, listen to the podcast and read the "Seconds" one day later. After all, the things Carl and I discuss on the air won't reappear here, they are "SHR exclusives", so to say ;-)

Apropos, in yesterday's show, the topics we did cover were

• premature ejaculation, and how only two hormones seem to make a difference,  
• peptides as prostate cancer vaccine, and how Harvard scientists build them from scratch,
• supps vs. medications, and how fatal commonly overlooked interactions can be, and
• copper, and why it may well matter than raw milk has 2-3x more than pasteurized milk

and before we go on with the actual "seconds", I must acquit myself of a promise -- the promise to provide you with more information on #3 on the above list.

Supplemental data: Supplement vs. drug interactions

Figure 1: Important supplement drug interactions based on Tsai (2013)

Those of you who have already listened to the podcast will probably be waiting eagerly for the supplemental material with more information about the potential pitfalls with supplement-drug interactions, Carl and I have been talking about on yesterday's show. With some digging, typing, searching, excerpting and formatting on my part, I have actually come up with a quite comprehensive and for people who are not familiar with all the funky drug names, probably even more understandable version (see figure 1) of the tabular overview H.H. Tsai and colleagues from the China Medical University Hospital and the College of Pharmacy at the University of Illinois at Chicago have included in their latest review of the literature (Tsai. 2013).

What I left out are the two pages (!) part on St. John's wort. With 147 drug (!) interaction ranging from "A" as in "amiodarone" to "W" as in "warfarin" and covering almost every drug type from anti-depressants, protease inhibotors, calcium channel blockers, PDE-5 inhibitors (viagra & co), SERMs, proton pump inhibitors, etc.. In view of the fact that these are only the known interactions, it would be easier to list those drugs with which St John's does not conflict, anyway. So, unless you have a study at hand which conclusively shows that St. John's is no problem, I would rather err on the side of caution, than end up in the ER.

Top 5 of the most frequent interactions observed with medication that act on (ranked by frequency, figure in brackets indicates percentage of all drugs in the study; based on Lin. 2013):

1. nervous system (19.6%)
2. cardiovascular system (17.7%)
3. antiinfectives for systemic use (14.7%)
4. alimentary tract and and immunomodulating agents (12.2%)
5. musko-skeletal system (6.4%)

As far as the supplement list in figure 1 goes, the most frequent potential side effect due to supplement-drug interactions affected drugs / supplements that play a role in blood coagulation. Danshen, evening primrose, gingko, glucosamine, white willow bark, garlic, vitamin E, fish oil to name only the most common ones, they all can increase the risk of bleeding not only, but specifically in patients who are taking warfarin (aspirin, ibuprofen, heparin and others were on the list, as well).

"What’s wrong with telling a patient, 'If you don’t hear from us with your lab results a few days, give us a call'? The answer is plenty, if that patient is receiving warfarin therapy. Because warfarin has a narrow therapeutic range and complex pharmacology, insufficient monitoring or errors in dosing can lead to severe and possibly life-threatening bleeding and clotting in patients receiving it." (Bush. 2002)

In view of the "top 5" above, this certainly sounds counter-intuitive, but we are dealing with a practical research bias here. As I mentioned on the air, there is simply an overabundance of research on potential interaction with warfarin, because finding the right dosage and adapting it appropriately is already hard even when there are no confounding variables, so that a sudden supplement-drug interaction and subsequent increase in the risk of bleeding can potentially be fatal (see the quote in the red box to the right)!

Regardless of what medication you may be on, rules that apply for a healthy individual that does not take any medication chronically (not even 'harmless' NSAIDs), don't apply to you! So please for one, follow the recommendation you find on each and every supplement to "talk to your medical practitioner" before you add another 'harmless' supplement on top of the 'harmless' over-the-counter or prescription drugs you are taking.

The Seconds: Interesting news that have been missing from yesterday's show

After this pretty lengthy addendum, let's get to three other items I had actually planned to have on the show, two of them are exercise, while the third one is a health and supplementation... and, when I come to think about it, obviously also diet related news-item:

• Exercise makes you happy and puts an end to the greed for money! That's not exactly the result of a recently conducted study from the Charité in Berlin (Bothe. 2013), but it is more or less what follows from the differential response Bothe et al. observed in their untrained and highly trained subjects to monetary stimuli after they had completed a standardized running exercise (30 min at 60-70 % VO2max, T) or placebo (P).
  

  

  Who would have thought that: Exercise reduces the anticipatory response to monitary incentive delay (MIT) test (Bothe. 2013)

  "Acute exercise was found to influence gain anticipation. In the P compared to the T group a more pronounced anticipation-related BOLD response was found in mesolimbic and mesocortical dopamine-innervated regions like the VS, hippocampus (Hipp) and subgenual anterior cingulate cortex (sgACC). [...] Additionally, several brain structures potentially associated with motor preparation (primary and supplementary motor areas) as well as structures belonging to the ventral (lingual gyrus) and dorsal (cuneus, precuneus) visual pathway showed stronger BOLD responses to gain anticipation in the P group compared with the T group." (Bothe. 2013)

  Moreover, according to the paper which is going to be published in one of the upcoming issues of Medicine and Science in Sports and Exercise, all 43 healthy men between the age of  20 - 32 years who participated in the study showed similar increases in mood (effect size F=11.70).
  
  With both, the beneficial outcome of the positive and negative affect schedule and the decrease in anticipatory signalling (= the greedy "I am about to win!") in the psychological testing session (the so-called monetary incentive delay) in an fMRI brain scanner, being identical it becomes evident that you don't have to be an athlete to monetize (all puns intended ;-) on the beneficial psychological effects of exercise.

• 

  Figure 1: Changes in total lean mass, aerobic fitness, strength (mind the scaling with x10!), right ventricular mass and end-diastolic volume in subjects in the endurance (runners) and strength training arm (O-lifting) of the 24-week study (based on Spence. 2013)

  Changes to the heart (right ventricular) due to exercise are mild, and if anything more pronounced in response to endurance than resistance training! " Left ventricular (LV) adaptation to exercise training has been the focus of 'athlete's heart' research to-date, information regarding right ventricular (RV) adaptation is sparse, due to its complex structure and imaging technique limitations." (Spence. 2013) So scarce, in fact, that this recent study that has been conducted by researchers form the The University of Western Australia, the University of Leeds, a and the Liverpool John Moore's University is the first to take a closer look at the impact endurance or resistance training have on the morphology of the RV.
  
  For their randomized trial, the researchers recruited twenty-three young untrained men.. The men were assigned to either
  
  • endurance training (E; n = 10)  - consisting of a progressively overloaded program of walking/jogging/running, divided into three training phases over the 24-week period, or
  • resistance training (R; n = 13) - with a focus on periodised R program was Olympic weightlifting with incorporated assistance exercises (e.g. deadlift, squat, bench press, overhead press) to develop overall strength and technique
  for a total timespan of 6 months, in the course of which body composition, aerobic fitness, muscular strength, RV morphology (MRI) and function (speckle tracking echocardiography) were continously monitored.
  
  The results Spence et al. are going to publish in one of the future issues of Medicine and Science in Sports and Exercise refute even two pieces of common "knowledge". Firstly, a still totally benign, right ventricular hypertrophy was exclusively observed in the endurance training group, yet not in the heavy lifters who were doing their squats, deadlifts and military presses (by 2.7g following E and by 1.4 g  following R training). Secondly, both strength and size gains were no prerogative of the lifting weight group. Contrary to the increase in total lean mass (+1.3 kg vs. +2.1 kg), the strength increase of +53.8 kg vs. +35.3 kg was yet much significantly more pronounced in the weight lifters.
  
  On the other hand only the endurance training group saw significant statistically improvements in their aerobic fitness level. This correspondence of endurance exercise, mild ventricular hypertrophy and increased fitness levels is unquestionably telling in terms of "how bad" a physiologically enlarged heart where the ratio of left-to-right ventricular  mass remains intact (which was the case in the study at hand), don't you think so?
• Omega-3s, omega-6s, telomere length, CYP enzymes, endogenous cannabinoid and the liver you need all of them to see the complete picture While the epidemiologists are still debating who will and who won't benefit from omega-3 supplementation, those who still care about how our bodies works and why their colleagues over at the epidemiology department are still debating, have made quite some progress as far as the underlying health benefits of rectifying the omega-3 to omega-6 balance are concerned.
  
  
  Why are endocannabinoids problematic? One of the answers is: "They will make you fat!" Basically we have known that forever, but a recent study which tracked the conversion of dietary linolic acid (n-6) to it's endocannabinoid metabolits, 2-AG and anandamide has recently confirmed not just that, but also that the provision of no more than 1% of the total energy of the diet in form of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) can already make a huge difference (Alvhem. 2013). With the addition of the long-chain omega-3s, the rodents in the study had a 8:1 ratio of linolic acid (LA) to long-chain omega-3 fatty acids in their diets. Still much higher than what you will hear is necessary, but sufficient to reverse the overabundance of arachidonic acid, in the phospholipids of liver and erythroctes, and the +200% increase in endocannabinoid levels that had been brought about, when the researchers had increased the linolic acid content of the diet from 1% to 8% of the total energy intake. In view of the fact that the same goes for the increased food intake, feed efficiency, and adiposity the mice had developed on the 60% fat (total) diet with a high linolic acid content, this study - despite being done on rodents - clearly shows that it does not necessarily have to be a 1:1 ratio to grasp major health benefits.
  
  If you get down from  30:1 to 8:1 you've come a tremendous way, already; and guess what: The easiest way to achieve that is to just cut out all seed and vegetable oils as well as processed foods that contain them.
  In a recent review on the differential effects of fatty acids on human metabolism in the Italian journal Medical and surgical pediatrics G. Caramia emphasizes the role of omega-6 derived endocannabinoids:
  

  "[E]ndocannabinoids like anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol [that arise from the enzymatic conversion of linolic acid by enzymes from the cytochrome P450 family at the liver are] capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous cannabinoids' by binding and functionally activating one or both [of the] cannabinoid receptor present on nervous and peripheral cell membranes." (Caramia. 2013; my emphases)

  Unfortunately, the same enzymes which are responsible for the generation of those endocannabinoids, are also responsible for the conversion of n-3 PUFAs into more potent metabolites of EPA and DHA, which will actually do most of the the vascular- and cardioprotective magic that is commonly ascribed to "fish oil".
  
  And how does all that relate to telomeres?
  
  These competitive effects in turn segue directly into the observations of a double-blind 4-month trial that involved 106 healthy sedentary overweight middle-aged and older adults. The participants supplemented their diets with capsules containing either (1) 2.5 g/day n-3 PUFAs, (2) 1.25 g/day n-3 PUFAs, or (3) a placebo that mirrored the proportions of fatty acids in the typical American diet.
  
  Now, it's not news that this led to decreases in inflammatory markers. I am not going to bore you with those, don't worry!
  
  What is news, and in my eyes very important, is that neither the provision nor the dosage of additional long-chain omega-3s had an effect on telomere length, the only variable that mattered was were the changes in the n-6:n-3 PUFA plasma ratios, which "helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios (p= 0.02)" (Kiecolt-Glaser. 2013).

That's it as far as today's seconds go... you want more? Man, I could certainly give you more, but you know that gluttony was once considered a sin, right? Tomorrow is another day, and if you can't wait, just head over to the SuppVersity Facebook wall, which is always bursting from the seems with the latest tidbits from the realms of health, exercise and nutrition sciences.  

References:

• Alvheim AR, Malde MK, Osei-Hyiaman D, Hong Lin Y, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR. Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Obesity (Silver Spring). 2013 Oct;20(10):1984-94.
• Bothe N, Zschucke E, Dimeo F, Heinz A, Wüstenberg T, Ströhle A. Acute Exercise Influences Reward Processing in Highly Trained and Untrained Men. Med Sci Sports Exerc. 2013 Oct 10.
• Bush J. Preventing errors in your practice. Reducing risks for patients receiving warfarin. Fam Pract Manag. 2002 Jul-Aug;9(7):35-38.
• Caramia G. [Essential fatty acids and lipid mediators. Endocannabinoids]. Pediatr Med Chir. 2013 Mar-Apr;34(2):65-72.
• Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J, Glaser R, Malarkey WB, Hwang BS, Blackburn E. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2013 Sep 23. pii: S0889-1591(12)00431-X.
• Spence AL, Carter HH, Murray CP, Oxborough D, Naylor LH, George KP, Green DJ. MRI-derived Right Ventricular Adaptations to Endurance versus Resistance Training. Med Sci Sports Exerc. 2013 Oct 15.
• Tsai HH, Lin HW, Simon Pickard A, Tsai HY, Mahady GB. Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review. Int J Clin Pract. 2013 Nov;66(11):1056-1078.

High Dose Omega-3 for Fat Loss? With 90% Lower Body Fat EPA Takes The Lead, DHA Second, ALA Distant Third... in Rats on Cornstarch or High Fat + High Sugar Diets

For Neo in the Matrix (courtesy of Warner Bros.) the choice was comparably easy. He had only two pills! You, however got to chose between ALA, EPA, DHA and, believe it or not, taking no pill at all!

I guess, those of you who are curious about the whereabouts of "your's truly" Adelfo Cerame Jr. will be disappointed to hear that he is currently so overwhelmed with clients and other duties that we have decided to turn the weekly contest prep series into a bi-weekly one.

Since this was more or less a last-minute decision, I just picked the next best study from my "interesting finds" folder and ... it turns out to be one of your, yet certainly not my favorite topics: Omega-3 fatty acids! That I am still skeptic about the usefulness, let alone necessity of respective supplements, does yet not change mean that I am deliberately ignoring interesting research on the unquestionable beneficial effects they have on lazy couch-potatoes and respective rodent models.

ALA, EPA, DHA - different acronyms, different effects?

Speaking of rodents, the soon-to-be published study by Hemant Poudyal, Sunil K. Panchal, Leigh C. Ward and Lindsay Brown from the Universities of Queensland and Southern Queensland in Australia unquestionably belongs into this latter category of "interesting rodent research on the benefits omega-3 fatty acids" (Pudyal. 2013). In order to differentiate the effects of alpha linoleic acid (ALA), the short(er)-chain brother to the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) people often falsely refer to as "fish oil" (while fish oil contains them, the average fish oil cap has ~40% EPA/DHA or 400mg in a 1g gel cap), the scientists assigned 96 male Wistar rats (9–10 weeks old) randomly to one out of 8 different diets containing

Carbohydrate, fat and protein content (rel. to total energy)

• corn starch,
• corn starch +1.1g/d ALA-rich chia oil,
• corn starch +0.7g/d EPA,
• corn starch +0.8g/d DHA, or
• high-carbohydrate, high-fat, 
• high carbohydrate, high-fat +0.7g/d ALA-rich chia oil 
• high-carbohydrate, high-fat +0.7g/d EPA oil and 
• high-carbohydrate, high-fat+0.6g/d DHA oil

The n-3 PUFA supplemented diets were prepared by adding 3% of the oil replacing an equivalent amount of water in the diet. n-3 PUFA supplemented diets were administered for 8 weeks starting 8 weeks after the initiation of the corn starch or high-carbohydrate, high-fat diet. The drinking water in all high-carbohydrate, high-fat fed groups was augmented with 25% fructose for the duration of the study.

Profound anti-obesity effects of EPA and DHA

Over the course of the 8-week supplementation period the researchers took daily measurements of body weight, food and water intakes. They performed two oral glucose (OGTT) and insulin tolerance tests (ITT) before and after the 16 weeks trial and measured the body composition by Dual-energy X-ray absorptiometric (DXA).

Figure 1: Body composition, lipid profile, glucose management (left to right) in rodents after 8 weeks on chia seed oil (ALA), EPA and DHA supplemented diets (date expressed relative to cornstarch non-supplemented control; calculated based on Poudyal. 2013)

If you take a look at my plot of the data, you may be surprised about the significance of the results. While it has to be said that even the "normal" control diet was not exactly what I would deem healthy (even for a rodent), it is nevertheless astonishing how pronounced the anti-obesity effects actually were.

Downstream benefits on organ health, ...

Figure 2: Contrary to what we have seen in previous studies (see TTA+fish oil), the high doses of the different omega-3s (HED ~20-30g!) had no effect negative effects on either the transaminase (ALT, AST), lactate dehydrogenase (LDH), alkaline phosphatease (ALP) or bilirubin values or the histology (histologies of hepatcytes not shown) of the liver of the rodents (data based on Poudyal. 2013)

Compared to the effects of the high doses of long-chain omega-3s the ALA treatment had a comparatively low impact on the adiposity. This could partly be a result of the fact that the omega-3 fatty acid metabolism in skeletal muscle and adipose tissue appears to be specific. While EPA and DHA
accumulated readily in these organs, when they were directly supplemented, the provision of ALA did not increase the contents of long-chain omega-3 fatty acids in either body fat or skeletal muscle tissue.

On the other hand, all omega-3 fatty acids showed beneficial effects on heart and liver the function of which had already been compromised by the 8 weeks on the extreme high carbohydrate or high sugar + high fat diet (reduced cardiac fibrosis, hepatic steatosis and inflammation in both the heart and the liver). In that, both, both, the improvements in body composition, as well as organ health, were more pronounced in the low-fat diet compared to the high-carbohydrate, high-fat diet.

... but negative effects on glucose management

Against that background it is actually surprising that none of the omega-3 fatty acids actually did what they are often hailed for: Neither ALA, nor EPA or DHA did improve the profoundly reduced glucose tolerance of the carb-o-holic rodents. On the contrary,...

"[...] EPA and DHA supplementation increased basal blood glucose concentrations, decreased intestinal glucose absorption and maintained the blood glucose concentrations for two hours after glucose loading with normal insulin sensitivity." (Poudyal. 2013)

Interestingly, this effect was probably brought about by yet another unexpected effect the high dose (human equivalent ~20-30g) omega-3 treatment had on the sympathetic nervous system:

"These effects were accompanied by increases in sympathetic activation seen as increased heart rate and cardiac output, increased force of left ventricular contraction and increased vascular responses to noradrenaline and sodium nitroprusside as observed with the hypothalamus–pituitary– adrenal axis response to stress and low blood glucose concentrations " (Poudyal. 2013; my emphasis)

As Poudyal et al. point out, this could also explain the profound weight loss effect in the cornstarch groups, and the "relatively smaller but significant changes in [high fat + high sugar] rats that still have an abundance of fructose and fat to meet the energy requirements."

From rodents to humans, from humans to...  fishmen?

The latest on the usefulness of omega-3 supplementation for active individuals and athletes: One of the most recent reviews of the issue states: "[O]nly a few studies have evaluated the impact of omega-3 PUFA supplementation on exercise performance. It has been suggested that the ingestion of DHA of approximately 1-2 g per day, at a ratio of EPA to DHA of 2:1, may be beneficial in counteracting exercise-induced inflammation and for the overall health of an athlete. However, the human data is inconclusive as to whether omega-3 PUFA supplementation, at this dosage, is effective in attenuating the inflammatory and immunomodulatory response to exercise, and improve exercise performance." (Micleborough. 2013; my emphasis)

These (at least for me novel) effects of very high doses of EPA and DHA on the sympathetic nervous system as well as the modulatory effects of the baseline diet are certainly things to keep in mind. This is particularly true in view of the latest epidemiological data which suggests that the consumption of comparatively minuscule amounts of fish oil has a population (and thus probably diet-)dependent effect on diabetes risk  (Wallin. 2013), with

• 17% increased risk of type-2 diabetes per 0.30 g per day increment in long-chain n-3 fatty acids in US residents, and
• -2% reduced risk of type-2 diabetes per 0.30 g per day increment in long-chain n-3 fatty acids in Europeans

The same goes for the U-shaped dose-response curve, Crochemore observed in one of the most recent controlled trials in the course of which a low dose (1.5 g/d) fish oil supplement improved the body composition and fatty acid metabolism of 41 women (60.64 ± 7.82 years) with high blood pressure and diabetes mellitus, while only 1g more, i.e. 2.5g/day, did not simply yield less pronounced decreases in body mass and waist circumference, the "high" dose fish oil supplement also reduced the already highly compromised insulin sensitivity of subjects even further (Crochemore. 2013).

EPA & DHA can come to the rescue, but a healthy diet would render supplements obsolete

If I did not know that fish oil was an invention of the 1990s, I would speculate that the "fishman" in the 1954 horror blockbuster The Creature from the Black Lagoon (Universal Pictures) was a "fish oil fat loss supplementation experiment gone wrong" ;-) Or joke aside - you don't seriously consider popping 70 fish oil caps a day to get the human equivalent of the ~1g of EPA or DHA the rodents in the study consumed, do you?

Regardless of the "optimal dosage", we should not lose sight of the influence and importance of the basal diet, when we evaluate the effects of DHA and EPA on body composition, lipid metabolism and not the least glucose management. It is, for example, very unlikely that we would see anywhere similarly pronounced effects in humans who are following a whole-foods based, "paleo-esque" diet without tons of cornstarch in it (control group), or plain sugar (and 17% additional fructose) that are on top of that hilariously protein-deficient (5%-6% is - if anything - enough not to die).

If you chose grass-fed over regular butter / dairy (makes sense only for high fat dairy), eat fish once or twice a week and replace the grain-based oils in your diet with coconut and olive oil, anything that goes beyond the occasional one or two fish oil caps will probably do more harm than good. And let's be honest, you don't really believe that you would get rid of the blubber that may still be covering your abs by copying the supplementation protocol of the study at hand and taking 70 fish oil caps every day to get your 20-30g of EPA and DHA, do you?

References:

• Crochemore IC, Souza AF, de Souza AC, Rosado EL. ω-3 polyunsaturated fatty acid supplementation does not influence body composition, insulin resistance, and lipemia in women with type 2 diabetes and obesity. Nutr Clin Pract. 2013 Aug;27(4):553-60.
• Mickleborough TD. Omega-3 Polyunsaturated Fatty Acids in Physical Performance Optimization. Int J Sport Nutr Exerc Metab. 2013 Sep 4.
• Poudyal H, Panchal SK, Ward LC, Brown L. Effects of ALA, EPA and DHA in high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. J Nutr Biochem. 2013 Sep 28. pii: S0955-2863(12)00207-0. .
• Wallin A, Di Giuseppe D, Orsini N, Patel PS, Forouhi NG, Wolk A. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care. 2013 Apr;35(4):918-29.

Mercury in Fish NOT Harmless, Regardless of Cysteine, Selenium, EPA or DHA! Plus: No Cardioprotective Effect of Omega-3 in Men With Higher Hair Mercury Levels

Image 1: Nice! Luckily nothing you will catch everyday, because if you ate this little bastard, a Tile Fish from the Gulf of Mexico, everyday, you could - in the worst case - be consuming 933µg of mercury with every 250g serving!

"Mercury from fish is not a problem, because you get plenty of selenium to counter it... moreover it's mostly protein bound, already..." - Another Myth Busted!? I must admit, I did believe (without ever checking scientific references) the common mantra that the mercury (Hg) content of fish would not actually be a problem, as long as there is enough selenium (Se) in the fish to "buffer" the Hg load. Now, this certainly makes sense and even very recent studies confirm that the effective uptake is reduced with higher Se:Hg ratios (e.g. Calatayud. 2013). Moreover, the notion that selenium exerts a protective effect is bolstered by data from various indigenous populations in the Brazilian Amazon (Lemire. 2011).

Cysteine, Omega-3 & Selenium? Won't help!

Unfortunately, a recent study by a group of scientists from the Arcachon Marine Station in Acachon, France, does now remind me why I have made it a rule over the year to question every conventional wisdom regardless how logical it may seem (Bourdineaud. 2013). The researchers fed a group of mice diets that contained either 4.88% fishmeal powder that had been produced from the flesh of H. aimara fish that had been caught in the Sinnamary River in French Guiana and contained 5µg Hg/g or a control diet which had slightly less protein (14.2% vs. 18.1%) and contained higher concentrations of EPA(10x), DHA(>30x) and DPA (>5x) - obviously right from the fish.

Figure 1: Fatty acid composition of the diets (left) and breakdown of the omega-3 part of the diets (rel. to total PUFA content - right; data calculated based on Bourdineaud. 2013)

In addition, the fish diet contained methylmercury in its purportedly less toxic largely peptide bound form, methylmercury-cysteine (MeHg-cysteine), while the mercury the scientists had added to the control diet was the purportedly more toxic salt form of mercury, i.e. methylmercury-chloride (MeHgCl).

Which fish contains how much mercury? I knew you would ask this and in essence it is impossible to answer without analyzing the very same fish, because as we are about to see, even the same species from the same fishing ground won't do.

Figure 2:  Mean (bottom axis!) and max (top axis!) mercury content (mg/kg) in fish (based on FDA Monitoring Program. 1990-2010)

Now, I would be a hilarious smartass if I left you with this "you never know" statement, but would still advice you to regard the following information as very broad estimations and heavily generalized categorizations:

• the worst offenders: Mackerel, King Shark, Swordfish & Tilefish (from the Gulf of Mexico) with mercury levels in the 1,000µg/kg range - 250g of those and you are on par with the mice in the study
• examples from the rest of the pack (see figure 2): It is plain to see that even fish with a relatively low mean mercury concentration such as Pollock (mean: 31µg/kg) can be laden with mercury, if you just pick the wrong one (max: 780µg/kg!)

Regardless of in some cases 20x higher outliers, you are probably on the safer side of things, when you pick one of the fish / shellfish that are on top of figure 2 and thus have the lowest mean mercury concentration.

How much did the mice consume? With  253 and. 237µg/kg in the MeHgCl and fish diets the mice in the study at hand consumed ~1µgof mercury per day this corresponds to a human equivalent dose of approximately 3.2µg/kg or 263µg/day for a 80kg adult.

Next to the aformentioned selenium argument (the selenium content of the fish diet was likewise higher 480 vs. 300µg/kg), the presence of MeHg-cysteine instead of MeHgCl and the healthy fish oils, are arguments #2 and #3 in the unquestionably convincing "mercury from fish is not a problem" argument.

It takes 8 weeks of mercury expose for the mice to go havoc - only from fish, though!

The mice were maintained on the diets for either 29 or 58 days. At the end of the exposure period, mice were subjected to an open-field maze test, in order to quantify anxiety levels, and to a Y-shaped maze test, to assess cognitive ability. Thereafter, the rodents were anesthetized and tissue samples were taken. Here are the main findings:

• within the first 10 days of the feeding period, the mice on the Hg containing diets gained  weight faster than rodents on a non-Hg control diet - 4%  and 7.4% more weight gain in the MeHgCl and Fish group, respectively; afterwards the weight development was identical
• both Hg diets lead to significant increases in serum and tissue MeHg with the kidneys being the "preferred" storage place with a tissue concentration of 7.3 and 6.8mgHg/g in mice fed the MeHgCl and fish diets, respectively (17x and 16x higher than in controls); there was a statistically significant inter-group difference only in the striatum, which accumulated ~30% less methylmercury in the fish group compared to the MeHgCl group
• significant behavioral abnomalies did only occur on the 2nd test at the end of the study period (day 58) and were exclusive to the Fish group, which also exhibited an increased dopamine metabolic turnover in the hippocampus

In the end, there is little to add to the scientists somewhat disillusioned conclusion that despite the fact that they had had good reason to assume (like you and I ;-) that the mercury induced metabolic and neurocrine perturbations in the Fish group "should appear less severe than that observed with the MeHg-containing diet [..] the present study" falsified the original hypothesis and suggests that rather than being less toxic, the peptide bound MeHgCysteine in fish is even more toxic than its chloride bound counterpart.

"Mice are nice, but what about men? I am sure know fish oil protects us!" Not really, no...

Another of the pieces that's still missing to get at least a preliminary grasp of the fish oil, selenium, mercury-toxicity puzzle, comes from a recent study that's been conducted at the University of Eastern Finland in Kuopio, and in the course of which the scientists analyzed the relation of mercury exposure (as quantified by hair mercury levels), long-chain poly-unsaturated fatty acids (LC-PUFA = omega-3) levels and individual risk of CVD, in general, and sudden cardiac death, in particular, in a group of 42-60 year-old men who had been free of any adverse cardiovascular events at baseline in 1984-1989 (Virtanen. 2013); and the results Virtanen et al. present in a paper in the July edition of the free medical Journal PloS One are astonishing, to say the least:

• of the three long-chain polyunsaturated fatty acids, EPA, DHA and DPA (=docosapentaenoic acid), only the latter, i.e. DPA, correlated significantly with the absence of sudden cardiac death within the time to the follow up (p < 0.01)
• the by far best predictor of whether or not the study participants would pass away before their time was yet the hair mercury content, which was 53% higher in those unlucky 91 patients who died from sudden cardiac death, than in the "survivor" group (2.85µg/g vs. 1.86µg/g)

Before we take a closer look at how this translates into the calculated hazard risks, I do yet feel inclined to draw your attention to some more basic, and not statistically processed baseline characteristics of the participants with the highest (4.96–15.59%) serum LC-PUFA values.

Don't deduce from pairs of associations!

A brief lesson in interpretation of scientific data - If A & B, and A & C, then B & C... NO!

Actually this thing about associations and logical reasoning is nothing extraordinary, but I thought it may be worth reminding you not to make the false assumption that  "if A is associated with B and A is associated with C, then B must be associated with C, as well", or to give you a more concrete example: If people with high LC-PUFA levels have higher incomes and people with high LC-PUFA levels have higher mercury levels, then people with higher mercury levels should also have higher incomes"

I see, now you are laughing, but I bet, everyone of us has once fallen for a similar mistake, esp. if the result of this falsely applied deduction was in support of your original hypothesis.

The study participants with the highest long-chain omega-3 levels in their blood also had the highest...

• physical activity (borderline significant p = 0.06)
• income (p < 0.001) and eduction (p = 0.01)
• fish, fruit, berry and vegetable intakes (p < 0.001)
  
• the highest hair mercury concentration (p < 0.001)
• the highest alcohol intake (p < 0.001, and 53% more than those w/ 1.7-3.9% LCPUFA)
• the highest rates of coronary heart disease in the family (p = 0.03, but only 6% difference total)

Despite the fact that higher mercury levels in the had were thus obviously associated with higher omega-3 levels in the blood, it would be preliminary to assume that all other of these variables, such as a higher income, or the physical activity would also be associated with higher mercury levels. And in fact, the exact opposite is the case,...

• higher income,
• higher education,
• higher fruit and vegetable intake and
• higher physical activity
  

... all of which were also associated with higher omega-3 levels in the blood were statistically significantly associated with lower mercury levels!

Mercury, fish oil and heart disease a marvelous triumvirate 

Let's get back to the harzard ratios and how fish oil intake and methylmercury intoxication interact in terms of the sudden cardiac death risk of the middle-aged (mean age at baseline 52.1 years) study participants.

Figure 3: Hazard ratios relative to lowest - adjusted for age and examination year (model 1),  adjusted for model 1 and body mass index, pack-years of smoking and alcohol intake (model 2),  adjusted for model 2 and hair mercury content (model 3); and hazard ratios associated with each 0.5%  unit increase in serum LC-PUFA, stratified by the median hair mercury content (calculated based on model 2, right; data compiled based on Virtanen. 2013).

While there is certainly much that could be said about the overall study outcome, there are three things that are remarkable, novel and particularly noteworthy in the data in figure 3:

• EPA is not only useless, without additional statistical shenanigan, it is even associated  (yet non-significantly) with an increased risk of CVD, when it's really high (+2% risk increase for each unit increase in EPA).
• DHA is only protective, when the methylmercury levels are low (model 3 in figure 2 adjusts for that), when this is the case, however, each unit increase in DHA is associated with a whopping -19% decrease in
• the statistical significance of the protective effects of DPA against sudden cardiac death is lost, when the data is adjusted for body mass index, pack-years of smoking and alcohol intake.

If we take the interactions with the hair (and thus presumably bodily) mercury load into consideration (see figure 3, right), it becomes obvious that hair mercury levels above the >1.28mg/g range renders both EPA and DHA practicually useless.

"Where do I get this DPA from; and what's that anyway?"

Figure 4: Enzymatic cascade from ALA to DHA; if you take a closer look the cascade does also explain why an increased conversion of ALA can competitively reduce the generation of EPA (see Portolesi. 2007)

Unfortunately, EPA and DHA are the two major forms of long-chain omega-3 fatty acids you will find in supplemental and dietary fish oil, so that your body will have to derive the DPA via Δ5-desaturase from EPA on its own (Leslie. 1985; see my illustration in figure 4 to get an idea of the whole cascade). This is not impossible, but obviously a rate limited step that could be avoided by direct supplementation, which is in fact something Miller et al. have done, only recently, and, as you have read, right here at the SuppVersity (see "On Short Notice" from July 29, 2013), which remarkable success (Miller. 2013).

Whether the beneficial effects of DPA are in fact related to its "reservoir function", Miller and his colleagues speculate about, cannot be said but would certainly constitute an intriguing research question for another rodent trial, maybe the mice in the Bourdineaud study would have been normal if they had had more DPA in their diets (see figure 1, right)

Bottom line: Until more scientific data is available (and probably still thereafter), there are actually three practical implications from this study you should bear in mind: (1) It does not make sense for anyone who carelessly shovels down tons of potentially mercury loaden fish to freak out about a tiny amalgam filling; (2) if you intend to benefit from the cardioprotective effects of fish oil, you better make sure that you are getting supplements and fish that have been tested for mercury, because the selenium alone obviously won't do the trick and save your ass... ah, pardon, your heart ;-) and (3) if you don't eat the worst offenders on a daily basis the benefits will probably still outweigh the negatives: I have recommended to fatty fish once or twice a week numerous times in previous articles and I don't see why these results would change anything about the recommendation.

References:

• Bachmanov AA, Reed DR, Beauchamp GK, Tordoff MG. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet. 2002 Nov;32(6):435-43.
• Bourdineaud JP, Marumoto M, Yasutake A, Fujimura M. Dietary mercury exposure resulted in behavioral differences in mice contaminated with fish-associated methylmercury compared to methylmercury chloride added to diet. J Biomed Biotechnol. 2013;2013:681016. Epub 2013 Jul 26.  
• Calatayud M, Devesa V, Virseda JR, Barberá R, Montoro R, Vélez D. Mercury and selenium in fish and shellfish: Occurrence, bioaccessibility and uptake by Caco-2 cells. Food Chem Toxicol. 2013 Aug;50(8):2696-702. Epub 2013 May 22. 
• Lemire M, Fillion M, Frenette B, Passos CJ, Guimarães JR, Barbosa F Jr, Mergler D. Selenium from dietary sources and motor functions in the Brazilian Amazon. Neurotoxicology. 2011 Dec;32(6):944-53.
• Miller E, Kaur G, Larsen A, Loh SP, Linderborg K, Weisinger HS, Turchini GM, Cameron-Smith D, Sinclair AJ. A short-term n-3 DPA supplementation study in humans. Eur J Nutr. 2013 Jun 23.
• Portolesi R, Powell BC, Gibson RA. Competition between 24:5n-3 and ALA for Delta 6 desaturase may limit the accumulation of DHA in HepG2 cell membranes. J Lipid Res. 2007 Jul;48(7):1592-8. 
• Virtanen JK, Laukkanen JA, Mursu J, Voutilainen S, Tuomainen TP. Serum Long-Chain n-3 Polyunsaturated Fatty Acids, Mercury, and Risk of Sudden Cardiac Death in Men: A Prospective Population-Based Study. PLoS One. 2013;7(7):e41046.

On Short Notice: Oxytocin to Boost Testosterone & Block Cortisol? Exercise for Life-Extension? Which Tea for Metal-Chelation? Which Fat to Reduce Calorie Intake by ~30%?

Image 1: This is still my preferred way to boost oxytocin - regardless of possible ergolytic effects ;-)

Due to the sudden heat-wave over here in good old Germany I thought, I'd use these early morning hours to get another installment of "On Short Notice" on it's way before my brain dries out (or I drown in the public swimming pool ;-). I hope you enjoy the four items on the recent interest in intranasal the hormone modulating effects of oxytocin, it's effect on cortisol and progesterone, estradiol and (I know you were waiting for that ;-) testosterone, my early morning / late evening (depending on whether you see this from my or Wyatt's perspective) 'intellectual' exchange on the potential longevity effects of exercise and why it probably is not life-extending in the literal sense, the different antioxidant potency of green, black and white tea and their ability to chelate metals (=help to remove all not just "bad" metals from the body) and the best fat, DHA or MUFA to blunt appetite and help you stick to your diet.

Don't forget to come back later today (or maybe early tomorrow for some of you ;-), for a third installment of "On Short Notice", which will hopefully suffice to "get rid" of the stock I have... ah, I did not forget about the Circadian Rhythm Series, by the way, it's just that the SuppVersity rhythm got slightly out of sync ;-)

• 

  Figure 1: Effects of 26IU of intranasal oxytocin at rest on progesterone, estradiol and testosterone in healthy men (large; based on Gossen. 2013); effects of 24IU or 48IU of intranasal oxytocin administered before a steady state cardio session on cortisol levels in healthy young men (small; from Cardoso. 2013)

  Intranasal oxytocin to block cortisol & boost testosterone A whole series of studies has been published recently; all of them have one thing in common, they investigate the various physiological and psychological effects of oxytocin. Of these, the two studies by Gossen et al. and Cardoso et al. are yet probably of greatest interest for the average physical culturist. After all, the researchers from the Centre for Research in Human Development at the Concordia University in Quebec (Canada) were able to show that the administration of 24IU (not the higher dose of 48IU, though;see figure 1) effectively reduced the increase in cortisol in a 70% HRmax steady-state cardio session in 17 healthy young men (aged 18–3; mean ± SD; 23.1 ± 3.5), in the experiment they describe in their Aug 2013 paper in Psychoneuroendocrinology (Cardoso. 2013).
  And even though the German scientists from the University of Aachen report minimal, but statistically significant increases in testosterone in 8 young men (mean age 26.4 ± 2.6 years) at rest, 210min after the (likewise) intranasal administration of a minimally higher dose (26IU) of oxytocin (Gossen. 2013). Both of these observations are not just very similar to what your average natty test booster is supposed to do, their real-world effects are probably also as insignificant. Also, did you ever try to tear down the gym and rep out a couple of PRs a couple of minutes after having sexual intercourse? If so, you should actually be aware why oxytocin probably ain't the ideal pre-workout supplement - in this regard it is also somewhat unfortunate that Cardoso et al. did not do a real performance test (suggested read: "Will Sex Before A Competition Hamper Your Performance"; note: this is not about sex minutes before the competition ;-).
  And when it comes to building muscle, previous research from Phillips lab at McMasters University appears to suggest that blocking cortisol is a hilarious idea, anyway. After tall, cortisol was the only endocrine hormone the elevation of which in the vicinity of resistance training sessions showed a positive correlation (r=0.29, P=0.03 cf. West. 2011) with increases in lean muscle mass in the large-scale by West et a.
• Exercise gets rid of the junk in your body, but will it help increase your lifespan? Basically this could be the headline to an interesting exchange of thoughts, I just had with Wyatt Brown on the SuppVersity facebook wall - one I believe is well worth being "recorded" as a short news item. The discussion came about in response to me posting the link to a study by He et al. who found that the way exercise induces autophagy (=natural, healthy cell death) contributes to its beneficial effects in the prevention of all sort of ailments, above all cancer and neurological problems such as Alzeimer's & co, because it allows your body to get rid of the debris and junk that's accumulating from just living your life (no matter how healthy or unhealthy that may be). Since exercise is not the only thing that can ramp up autophagy, and caloric restriction (as in starving yourself to live longer) can do the same, Wyatt mused about whether or not you could achieve the same (more or less; for animals vs. humans) proven benefits of life-long caloric restriction by exercise.

  

  Image 2: Twin studies are one of the ways to identify whether genes or lifestyle are the fundamental determinants of how old we get. One of the consistent findings of the numerous pertinent studies is that lifestyle factors (diet, exercise, but also our outlook on life, friends and family!) determine how well we are able to use the time that our genes (or whoever you want) has granted us on earth. Not more, but not less, either: If 100 years are what we got, all exercise and healthy eating will allow us to make it to that age with great ease, not more... and let's be honest, if that was the biblical age of 100y, wouldn't it be ungrateful to ask for more?

  A very good question, indeed and one I do not have a definite answer to. In view of recent reviews of the role of exercise in the longevity of centenarians (the oldest of the old; cf. Venturelli. 2013), it does however seem more likely that exercise does not have direct effects on the life-span, but, as Huffman states, "[e]pidemiologic evidence in humans supports exercise as a strategy to reduce the risk of morbidity and mortality" (Hufmann. 2010). Unfortunately, a low mortality won't help you to make it past the 100 ± X years your genes have in stock for you. The insights into the genetic determinants from pertinent studies into single-nucleotide polymorphisms (SNPs ~ single gene variations) does support this notion (Sorensen. 2013): The oldest of the old don't stick out, because their genes protect them from premature death, but simply because their genes allow for more cell cycles to occur before the 'natural reserve'. We already know that telomere length is a fundamental determinant of this 'reserve', so that it is not really surprising that telomere length at birth is one of the most reliable predictors of longevity (Heidinger. 2013)!
  Now, if we just use a totally random number to use basic math to make us understand, what this means, we could say that your telemore length at birth may be sufficient to make it to age 100, assuming that it is not prematurely shortened or you are dying from whatever other "natural" (not accidents etc.) cause, such as cancer, metabolic syndrome, CVD etc., exercise will of course help you to make it to those 100 years, but when the say 100,000 total turn overs that your telomeres allow for are done, you are done as well - no matter how "healthy" you eat and how much you exercise in the 99.99 years before. If you complement this "preventive" (=mortality reducing) effect by literally living on the slow lane, i.e. downregulating all your metabolic processes by starving yourself, you will obviously slow down the turn-over rate, as well. For simplicity of the calculation we assume that all these processes are linear (which I can guarantee they are not) and you are eating so little that you achieve a 50% slow down. That would mean that your turn-over rate would be reduced from 1,000 / year to 500 / year. Your reserves would last 2x longer and, assuming you eat and exercise and thus decrease your mortality risk, will allow you to make it to the ueber-biblical age of 200years! Great? Well you decide...

• 

  Image 3: If you want to get rid of metals, white tea should be your tea of choice, if you are already low on iron, copper, zinc & co. you should at least drink it away from your meals, though.

  Different tea preparations different effects antioxidant activity and metal chelation ability  It is nothing new that green and black tea will have differential effects on your physiology. What is yet a novelty is a comparison of the antioxidant and metal chelating activity the exact same hand plucked leaves of a specific cultivar (in this case PC108, bred in Malawi, typically used for black CTC tea production) will have when it is used for the production of either white, two black (Orthodox and CTC; both methods produce leaves of fannings or dust grades that are commonly used in tea bags, CTC = crush + tear + curl is processed by machines, while orthodox usually involves a mixture of mashine and manual processing) or two green (w/ and w/out caffeine) teas - a comparison like the one Patricia Carloni and her colleagues present in their latest paper in Food Research International (Carloni. 2013).
  As you will probably have expected the least processed green tea exhibited the greatest, while the most processed CTC black tea the least antioxidant activity (green ≥ low-caffeine green > white ≥ black Orthodox > black CTC), what may come as a surprise though is the superiority of white tea in the metal chelation essay the scientists performed. Closely followed by the orthodox black tea, the CTC tea (<50% of the white tea metal chelating activity) and the two green teas (<25% of the white tea metal chelating activity).

• 

  Figure 2: Reduction in calorie intake on standardized breakfast 20min after the ingestion of 6ml of a lemon flavored oil emulsion and in the course of the day compared to no oil control (based on Harden. 2013)

  Fat satiety effects: DHA > Olive Oil (MUFA) > regular diet That would be the ranking according to the satiety effects of the different fatty acids, as elucidated in a recently published study in the British Journal of Nutrition (Harden. 2013). For their study, the researchers had recruited 18 healthy normal-weight men. In a single-blind, three-way crossover study design the subjects received a single 6ml dose of either DHA or oleic acid (olive oil is 60-80% oleic acid, alternatives would macadamia ~60% and high-oleic acid sunflower oil >82%) with lemon flavor. The day before, the subjects had consumed standardized diets. 20min after the ingestion of the emulsion, they had a standardized breakfast, went home and went about their regular daily business for the rest of the day.
  The telephone interviews the researchers conducted on the next day showed that the ingestion of the DHA emulsion had exerted an, as the researchers argue cholecystokinin (CCK) dependent, decrease in energy intake of -20% and -29% for the breakfast and the total daily energy intake, respectively. That would make DHA a pretty effective tool to stick to my often-suggested -20% caloric deficit when you're dieting - at least for healthy individuals. Whether this will work for the obese, let alone morbidly obese with their deranged satiety signaling remains to be seen, though.

As I mentioned in the introduction, already. This was not the last "On Short Notice" item for this weekend. So, digest this, have some sex to calm down (unless you are about to work out, obviously), and drink a cup of tea to increase your chance to make sure that your end is not arriving before it's time and you can come back for more ;-)

References

• Cardoso C, Ellenbogen MA, Orlando MA, Bacon SL, Joober R. Intranasal oxytocin attenuates the cortisol response to physical stress: A dose-response study. Psychoneuroendocrinology. 2013 Aug 10. 
• Carloni P, Tianob L, Padellab L, Bacchettic T, Customud C, Kayd A, Damian E. Antioxidant activity of white, green and black tea obtained from the same tea cultivar. Food Research International. 2013.
• Gossen A, Hahn A, Westphal L, Prinz S, Schultz RT, Gründer G, Spreckelmeyer KN. Oxytocin plasma concentrations after single intranasal oxytocin administration - A study in healthy men. Neuropeptides. 2013 Aug 9. 
• Harden CJ, Jones AN, Maya­Jimenez T, Barker ME, Hepburn NJ, Garaiova I, Plummer SF, Corfe BM. Effect of different long­chain fatty acids on cholecystokinin release in vitro and energy intake in free­living healthy males. British Journal of Nutrition. 2013; 108:755­-758
• He C, Sumpter R Jr, Levine B. Exercise induces autophagy in peripheral tissues and in the brain. Autophagy. 2013 Oct 1;8(10).
• Heidinger BJ, Blount JD, Boner W, Griffiths K, Metcalfe NB, Monaghan P. Telomere length in early life predicts lifespan. Proc Natl Acad Sci U S A. 2013 Jan 31;109(5):1743-8. Epub 2013 Jan 9.
• Huffman DM. Exercise as a calorie restriction mimetic: implications for improving healthy aging and longevity. Interdiscip Top Gerontol. 2010;37:157-74. Epub 2010 Aug 10. 
• Soerensen M. Genetic variation and human longevity. Dan Med J. 2013 May;59(5):B4454.
• Venturelli M, Schena F, Richardson RS. The role of exercise capacity in the health and longevity of centenarians. Maturitas. 2013 Aug 7.
• West DW, Phillips SM. Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. Eur J Appl Physiol. 2013 Jul;112(7):2693-702. Epub 2011 Nov 22.